Synthetic Life and New Humankind

Synthetic Life and New Humankind

XNA is synthetic DNA that's stronger than the real thing

 

by Robert T. Gonzalez

New research has brought us closer than ever to synthesizing entirely new forms of life. An international team of researchers has shown that artificial nucleic acids - called "XNAs" - can replicate and evolve, just like DNA and RNA.

We spoke to one of the researchers who made this breakthrough, to find out how it can affect everything from genetic research to the search for alien life.

The researchers, led by Philipp Holliger and Vitor Pinheiro, synthetic biologists at the Medical Research Council Laboratory of Molecular Biology in Cambridge, UK, say their findings have major implications in everything from biotherapeutics, to exobiology, to research into the origins of genetic information itself. This represents a huge breakthrough in the field of synthetic biology.

 

The "X" Stands for "Xeno"

 

Every organism on Earth relies on the same genetic building blocks: the information carried in DNA. But there is another class of genetic building block called "XNA" — a synthetic polymer that can carry the same information as DNA, but with a different assemblage of molecules.

The "X" in XNA stands for "xeno." Scientists use the xeno prefix to indicate that one of the ingredients typically found in the building blocks that make up RNA and DNA has been replaced by something different from what we find in nature — something "alien," if you will.

Strands of DNA and RNA are formed by stringing together long chains of molecules called nucleotides. A nucleotide is made up of three chemical components: a phosphate (labeled here in red), a five-carbon sugar group (labeled here in yellow, this can be either a deoxyribose sugar — which gives us the "D" in DNA — or a ribose sugar — hence the "R" in RNA), and one of five standard bases (adenine, guanine, cytosine, thymine or uracil, labeled in blue).

The molecules that piece together to form the six XNAs investigated by Pinheiro and his colleagues (pictured here) are almost identical to those of DNA and RNA, with one exception: in XNA nucleotides, the deoxyribose and ribose sugar groups of DNA and RNA (corresponding to the middle nucleotide component, labeled yellow in the diagram above) have been replaced. Some of these replacement molecules contain four carbons atoms instead of the standard five. Others cram in as many as seven carbons. FANA (pictured top right) even contains a fluorine atom. These substitutions make XNAs functionally and structurally analogous to DNA and RNA, but they also make them alien, unnatural, artificial.

 Information Storage vs Evolution

 

But scientists have been synthesizing XNA molecules for well over a decade. What makes the findings of Pinheiro and his colleagues so compelling isn't the XNA molecules themselves, it's what they've shown these alien molecules are capable of, namely: replication and evolution.

"Any polymer can store information," Pinheiro tells io9. What makes DNA and RNA unique, he says, "is that the information encoded in them [in the form of genes, for example] can be accessed and copied." Information that can be copied from one genetic polymer to another can be propagated; and genetic information that can be propagated is the basis for heredity — the passage of traits from parent to offspring.

In DNA and RNA, replication is facilitated by molecules called polymerases. Using a crafty genetic engineering technique called compartmentalized self-tagging (or "CST"), Pinheiro's team designed special polymerases that could not only synthesize XNA from a DNA template, but actually copy XNA back into DNA. The result was a genetic system that allowed for the replication and propagation of genetic information.

A simplified analogy reveals the strengths and weaknesses of this novel genetic system: You can think of a DNA strand like a classmate's lecture notes. DNA polymerase is the pen that lets you copy these notes directly to a new sheet of paper. But let's say your friend's notes are written in the "language" of XNA. Ideally, your XNA-based genetic system would have a pen that could copy these notes directly to a new sheet of paper. What Pinheiro's team did was create two distinct classes of writing utensil — one pen that copies your friend's XNA-notes into DNA-notes, and a second pen that converts those DNA notes back into XNA-notes.

Is it the most efficient method of replication? No. But it gets the job done. What's more, it does all this copying to and from DNA with a high degree of accuracy (after all, what good is replication if the copy looks nothing like the original?). The researchers achieved a replication fidelity ranging from 95% in LNA to as high as 99.6% in CeNA — the kind of accuracy Pinheiro says is essential for evolution:

"The potential for evolution is closely tied with how much information is being replicated and the error in that process," he explains. "The more error-prone… a genetic system is, the less information can be feasibly evolved." A genetic system as accurate as theirs, on the other hand, should be capable of evolution.

The researchers put this claim to the test by showing that XNA strands made up of the HNA xeno-nucleotides like the one pictured here could evolve into specific sequences capable of binding target molecules (like an RNA molecule, or a protein) tightly and specifically. Researchers call this guided evolution, and they've been doing it with natural DNA for some time. The fact that it can also be accomplished in the lab with synthetic DNA indicates that such a system could, in theory, work in a living organism.

"The HNA system we've developed," explains Pinheiro, is "robust enough for meaningful information to be stored, replicated and evolved."

 

A Step Toward Novel Lifeforms

The implications of the team's findings are numerous and far-reaching. For one thing, the study sheds significant light on the origins of life itself. In the past, investigations into XNA have been largely driven by the question of whether simpler genetic systems may have existed before the emergence of RNA and DNA; the fact that these XNAs appear to be capable of evolution adds to an ever-growing body of evidence of a genetic system predating DNA and RNA both.

Practical and therapeutic applications abound, as well. "The methodologies [we've developed] are a major step forward in enabling the development of nucleic acid treatments," says Pinheiro. Natural nucleic acids [i.e. DNA and RNA] can be forced to evolve so that they bind tightly and specifically to specific molecular targets. The problem is that these nucleic acids are unsuitable for therapeutic use because they are rapidly broken down by enzymes called nucleases. As a result, these evolved nucleic acid treatments have a short lifespan and have a difficult time reaching their therapeutic targets.

To get around this, Pinheiro says medicinal chemistry is used to modify evolved DNA sequences in an attempt to create a functional molecule that can still bind to a therapeutic target but resist nuclease degradation. But doing this is tough:

"Overall, this leads to high cost and a high failure rate for potential therapies - there is still only a single licenced [nucleic acid-based] drug on the market (Macugen)."

But all six of the XNAs studied by Pinheiro and his team are stronger than regular DNA or RNA, in that they're more resistant to degradation by biological nucleases.

As a result, these molecules would need little or no adaptation for therapeutic (or diagnostic) use. "Since these molecules can now be selected directly on XNA, medicinal chemistry should no longer be limiting," says Pinheiro. You could select a suitable XNA for its biocompatibility and therapeutic potential, and not worry about having it rapidly degrade inside the body.

Pinheiro also says the outcome of the research could even have a strong impact on exobiology:

In my view, exobiology looks for life in regions it cannot physically visit. In that context, it searches for tell tale signs of life that can be remotely monitored but it has only life on Earth as examples to identify such suitable markers. Based on extant biology, DNA and RNA are good candidates for such a search. However, by showing that other nucleic acids can also store information, replicate and evolve, our research may force a rethink as to whether DNA and RNA are the most suitable tell tale signs of life.

Of course, nothing would call the indispensability of DNA- or RNA-based life into question more than the generation of an entirely synthetic, alternative life form, built from the ground up entirely by XNA. Such an organism would require XNA capable of driving its own replication, without the aid of any biological molecules. Pinheiro says that's still a ways off. "Even in its simplest setup... it would be very challenging to develop an XNA system within a cell." Such a system would require XNA capable of self-replication, and capable of undergoing evolution in a self-sustained manner.

That said, his team's work represents a major step in the right direction. As the molecular machinery designed to manipulate XNAs grows, so, too, will the capacity for synthetic genetic systems to stand and operate on their own.

The researchers' findings are published in Science.
Top image via Shutterstock; XNA moieties via Science; all other images via Wikimedia Commons

How Artificial Chromosomes Could Transform Humanity

 

by George Dvorsky

Normally, an extra pair of chromosomes would be considered dangerous. But what if we could design our own? According to biologists, we could create custom-built chromosomes to fix a variety of health problems, and even give us new abilities. Here’s how a 24th pair of chromosomes could change our biologies forever.

To learn more about this incredible prospect, we spoke to biophysicist Gregory Stock. He is the Chief Science Officer of Ecoeos, a company that develops clinically-validated DNA tests to measure personal susceptibility to environmental toxins. Stock is also the author of Redesigning Humans: Choosing Our Genes, Changing Our Future, and the recently updated Book of Questions which is scheduled for release later this year.

But before we get into artificial human chromosomes (AHCs), let’s quickly review what chromosomes are in the first place.

 

Packages of Genetic Material

Chromosomes are packages of the genetic material located in our cells — the foundation of our basic biology as an organism. They’re not a recipe for us, but they do specify the sequence of events that lead to the development of mature organisms. Chromosomes offer a way for nuclear material to be packaged, protected, and maintained as it’s passed from cell to cell.

Different components of chromosomes are turned on and off in different contexts and in various parts of the body. There are anywhere from around 250 million bases on some chromosomes, down to about 50 million on others.

We humans have 23 pairs, for a total of 46. These structures are very tightly organized windings of DNA that become encoiled in a complicated way and allow for division each time a cell divides, so that each cell has the same complement of genetics.

There are two types: autosomal and sex chromosomes.

Sometimes, an added chromosome can be problematic. An extra chromosome 21 leads to trisomy, also known as Down syndrome. XXYY syndrome happens when males have an extra X and Y chromosome, leading to developmental delays, extra height, and learning disabilities.

 

Now With Added Function!

 

But adding extra chromosomes artificially won’t necessarily be a bad thing. And in fact, they could be quite advantageous. When inserted during the in vitro fertilization (IVF) stage, they could serve as remarkable and flexible platform for the insertion of genetics.

 “The main attraction of creating an artificial human chromosome is that they can be passed down from generation to generation,” says Stock. “There’s all sorts of mechanisms and structures in place that would allow for the division and faithful reproduction of those chromosomes.”

What’s more, he explains, physicians will be able to control the various elements of the genetic sequences. We’ll be able to turn them on or off, or even accelerate their expression. Certain chromosomes may be put in place to serve as a backup, or to function at a specific stage of a person’s life (such as during elderly years when existing genetics isn’t up to the task).

Stock says we could add an additional pair, bumping our total up to 24. Or, if we wanted to deploy them in discrete and tidy packages — which would contribute greatly to their flexibility — we could just keep adding pair after pair after pair. In fact, the technology to do this could come sooner rather than later, with chromosomes containing a mere 10 to 20 megabases.

“Ideally, if you were to create an extra chromosome, rather than putting extra genetic material and inserting it into an existing chromosome — where it might be put into a random spot or put into something else that’s going on — you have a very controlled environment,” he told io9. “You can create these things, duplicate them independently, and put them in different organisms. It’s a very controlled process.”

And in fact, this is already being done. The prospect got off the ground back in 1997 after John Harrington and Huntington Willard developed a technique for doing so. Bacterial artificial chromosomes are used in labs all the time, as are yeast ACs (called YACs). Biologists have even created ACs in mice. We’re currently at the nascent stage of human artificial chromosomes.

“When you start to think about the potential for architectural intervention in humans, an attractive feature is that it could be so controlled that you could make it conditional,” says Stock. “This way, you can turn the elements on or off and at different points — similar to the way it happens in the fine orchestration of genetic activity in the developmental process.”

Stock says that we’ll be able to put some new genetic material into a chromosome and not have to turn it on until the individual is an adult. As a result, we won’t be tampering with the very sensitive arena of human development — something that would prove to be far more difficult to manage in a fully mature adult.

He envisions the day when we’ll be able to use AHCs to increase human immune function, slow down the effects of aging — or even boost our memory and intelligence. They could serve a new form of immunization, protecting against specific diseases like AIDS or certain cancers.

AHCs could also give humans new capacities altogether. Stock speculates about a range of futuristic enhancements, including the ability to see ultraviolet light, or navigation in the dark by a system of sonar similar to that employed by bats.

 

Therapy or Enhancement?

 

I asked Dr. Stock if this could be considered a therapy or an enhancement. “Well, I’d call this a therapeutic enhancement,” he replied. “But ultimately it’s a matter of perspective.”

Indeed, some people might consider a super-juiced immune system that's triggered later in life as an enhancement. Same for chromosomal interventions that could extend a person’s lifespan. Others, on the other hand, might simply say it's just a different way of doing therapy.

“But it also depends on whether or not someone is on the lower or upper area of performance of a specific category,” he added. “If you have diminished function, then they’re likely to be considered enhancements.”

One important thing to remember about enhancement, says Stock, is that it’s going to be tough. Unlike the repairing of health problems, which tend to be simpler, enhancement will elevate performance, which could result in unintended and unforeseen consequences. “That will require us to get everything right,” he says.

Stock points to the controversial realm of IQ and cognitive enhancement.

If somebody is functioning with an IQ of 70 — which is a couple of standard deviations below average — that may be the result of some very specific developmental problems that occurred, or some other underlying issue that’s relatively easy to repair. That person, if it’s caught early enough, might end up having an average IQ — which would most certainly seem like an enhancement to them.

But if a person has an IQ of 160, which is way out in terms of normal function, we’d be hard pressed to enhance their performance without having some subtle, or not so subtle secondary consequences that would be very difficult to gauge.

“For example, super-bright people often have quirks in their personality that, depending on your viewpoint, is either a positive a negative,” adds Stock.

Altering Our ‘Genetic Heritage’?

 

Stock says that the limited enthusiasm behind AHCs is due to a number of other viable interventions that could basically do the same thing.

“Naturally, we’re going to do what’s the safest and most effective thing.”

He points to embryonic genetic screening and drug treatments. Or even using assistive devices, like mobile phones, to ‘enhance’ our memories.

“All our tight associations with technology make us functional cyborgs, in which case we’re really and truly enhancing ourselves — so there are only a very few applications in which there aren’t easier paths when compared to genetic enhancement.”

Stock also notes the potential for somatic engineering, in which the existing cells of adults can be modified by injecting short genetic sequences.

“But technologically it’s much easier in the embryo,” he says. “With artificial human chromosomes, they’re automatically present in every cell in the body, and it can be set up in ways in which it can be turned on and off locally, like taking a specific drug that triggers it.”

This is a very important issue, he adds, because it makes the entire system failsafe.

I asked Stock about the ethical concerns related to the potentially permanent modification of the human germ line.

“Yeah, the general tone of the discussion is, ‘How could you possibly do that!? You’re altering our genetic heritage, and you’re altering genetics in humans — because once you get into our genetics then it’ll be passed on to the next generation!’”

But Stock thinks this represents a fairly limited view of technology.

“The fear that future generations won’t be able to remove it, inactivate it, make it non-heritable, or replace it with something better seems to me to be a rather tortured scenario,” he says.

But looking at advanced technologies, and then representing the context of them as being stationary and very limited, doesn’t make a lot of sense to Stock. What’s more, these technologies will be tested in animal subjects. And in fact, an artificial human chromosome has already been injected in mice.

“My suspicion is that we wouldn’t be reproducing naturally once we’re in that state,” says Stock, “because there’s so much more that we’ll be able to do 25 years from now. And we’re definitely going to want the next generation of artificial chromosomes. These things tend to move very quickly.”

As for a timetable, Stock expects to see the first artificial human chromosome put to use in about a generation from now, perhaps in 20 years.

“Bioengineers tend to underestimate the complexity of human biology,” he says. “These developments often come at a slower pace than we imagine. But they’re inexorable.”

Image: Creations/Shutterstock; Alila Medical Images/Shutterstock; Tehelka.


From io9 @ http://io9.com/5903221/meet-xna-the-first-synthetic-dna-that-evolves-like-the-real-thing and http://io9.com/how-artificial-chromosomes-could-transform-humanity-754993569

For more information about synthetic life see http://nexusilluminati.blogspot.com/search/labelsynthetic%20life /
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